title: Effect of ruboxistaurin (RBX) On visual acuity decline over a 6-year period with cessation and reinstitution of therapy: results of an open-label extension of the Protein Kinase C Diabetic Retinopathy Study 2 (PKC-DRS2).
abstract: OBJECTIVE
  The PKC-DRS2 was a Phase 3, randomized, double-masked, placebo (PBO)-controlled, 3-year study of the effect of 32 mg/day of ruboxistaurin (RBX), an orally administered protein kinase C inhibitor, on vision loss in patients with moderate to severe nonproliferative diabetic retinopathy. Ruboxistaurin reduced the occurrence of sustained moderate visual loss (SMVL; ≥15-letter decline in visual acuity sustained for the last 6 months of study participation) from 9.1% in the PBO group (N = 340) to 5.5% in the RBX group (N = 345, P = 0.034). This study evaluates the primary end point of SMVL in a 2-year open-label extension (OLE) of the PKC-DRS2, which began a median of 466 days (range, 263-1,296 days) after the conclusion of PKC-DRS2.
  
  
  METHODS
  Visual acuity was measured by certified examiners using the Early Treatment Diabetic Retinopathy Study chart.
  
  
  RESULTS
  Of the 514 patients who completed PKC-DRS2, 366 did so in the 32 study centers participating in the OLE, and of these, 203 (55%) enrolled in the OLE for treatment with 32 mg/day of RBX for 2 years. Of the 203 enrolled in the OLE, 100 had previously been treated with PBO (prior PBO subgroup) and 103 had been treated with RBX (prior RBX subgroup). PKC-DRS2 baseline patient and ocular characteristics were well matched between these two subgroups and were similar to the PKC-DRS2 patient population as a whole. Using the PKC-DRS2 baseline as the starting point, SMVL occurred in 6% of the prior PBO subgroup during the PKC-DRS2, increasing to 26% by the end of the OLE. However, in the prior RBX subgroup, SMVL occurred in only 4% and 8% during the PKC-DRS2 and by the end of the OLE, respectively (P < 0.001 for difference at the end of the OLE). In the prior PBO subgroup, mean visual acuity declined from 79.6 letters at PKC-DRS2 baseline to 73.1 letters at OLE end point (-6.5 letters). In the prior RBX subgroup, this loss was 2.7 letters (79.8 to 77.1) over the same period (P = 0.02).
  
  
  CONCLUSIONS
  Over a 6-year study period incorporating 3 years of a rigorously placebo-controlled trial, approximately 1 year off treatment and 2-year OLE where all groups received therapy, those patients with greatest RBX exposure (∼5 years) experienced less SMVL compared with those in the original PBO group (∼2-year RBX exposure).
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA. msheetz@lilly.com
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Sheetz
authors.forename: Lloyd Paul
authors.initials: LP
authors.lastname: Aiello
authors.forename: Nazila
authors.initials: N
authors.lastname: Shahri
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Davis
authors.forename: Keri A
authors.initials: KA
authors.lastname: Kles
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Danis
mesh_terms: D000284:Administration, Oral; D003930:Diabetic Retinopathy / Q000188:drug therapy*; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D008297:Male; D008301:Maleimides / Q000627:therapeutic use*; D008875:Middle Aged; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D064546:Protein Kinase C beta; D019233:Retreatment; D014786:Vision Disorders / Q000188:drug therapy*; D014787:Vision Tests; D014792:Visual Acuity / Q000187:drug effects*; D028761:Withholding Treatment
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; C099154:ruboxistaurin; D011493:Protein Kinase C; D064546:Protein Kinase C beta